Pub Date : 2025-02-03DOI: 10.1016/j.dld.2025.01.189
Qingqing Dai, Quratul Ain, Navodita Seth, Michael Rooney, Alexander Zipprich
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the predominant liver disease and is becoming the paramount contributor to end-stage liver disease and liver-related deaths. Liver sinusoidal endothelial cells (LSECs) located between the hepatic parenchyma and blood from viscera and gastrointestinal tract are the gatekeepers for the hepatic microenvironment and normal function. In normal physiological conditions, LSECs govern the substance exchange between hepatic parenchyma and blood through dynamic regulation of fenestration and maintain the quiescent state of Kupffer cells (KCs) and hepatic stellate cells. In MASLD, lipotoxicity, insulin resistance, gastrointestinal microbiota dysbiosis, and mechanical compression caused by fat-laden hepatocytes result in LSECs capillarization and dysfunction. The altered LSECs progressively shift from healer to injurer, exacerbating liver inflammation and advancing liver fibrosis. This review focuses on the deteriorative roles of LSECs and related molecular mechanisms involved in MASLD and their contribution to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis development and progression. Furthermore, in this review, we propose that targeting LSECs dysfunction is a prospective therapeutic strategy to restore the physiological function of LSECs and mitigate MASLD progression.
{"title":"Liver sinusoidal endothelial cells: Friend or foe in metabolic dysfunction- associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis.","authors":"Qingqing Dai, Quratul Ain, Navodita Seth, Michael Rooney, Alexander Zipprich","doi":"10.1016/j.dld.2025.01.189","DOIUrl":"https://doi.org/10.1016/j.dld.2025.01.189","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the predominant liver disease and is becoming the paramount contributor to end-stage liver disease and liver-related deaths. Liver sinusoidal endothelial cells (LSECs) located between the hepatic parenchyma and blood from viscera and gastrointestinal tract are the gatekeepers for the hepatic microenvironment and normal function. In normal physiological conditions, LSECs govern the substance exchange between hepatic parenchyma and blood through dynamic regulation of fenestration and maintain the quiescent state of Kupffer cells (KCs) and hepatic stellate cells. In MASLD, lipotoxicity, insulin resistance, gastrointestinal microbiota dysbiosis, and mechanical compression caused by fat-laden hepatocytes result in LSECs capillarization and dysfunction. The altered LSECs progressively shift from healer to injurer, exacerbating liver inflammation and advancing liver fibrosis. This review focuses on the deteriorative roles of LSECs and related molecular mechanisms involved in MASLD and their contribution to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis development and progression. Furthermore, in this review, we propose that targeting LSECs dysfunction is a prospective therapeutic strategy to restore the physiological function of LSECs and mitigate MASLD progression.</p>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-03DOI: 10.1016/j.dld.2025.01.196
Longhu Li, Guangyao Li, Wangfeng Zhai
Background: Hepatocellular carcinoma (HCC) is a substantial global health challenge owing to its high mortality rate and limited therapeutic options. We aimed to develop an efferocytosis-related gene signature (ER.Sig) and conduct a transcriptomic analysis to predict the prognosis and immunotherapeutic responses of patients with HCC.
Methods: Single-cell RNA sequencing data and bulk RNA sequencing data were obtained from public databases. Based on single-sample gene set enrichment analysis and Weighted Gene Co-expression Network analyses, efferocytosis-related genes (ERGs) were selected at both the single-cell and bulk transcriptome levels. A machine-learning framework employing ten different algorithms was used to develop the ER.Sig. Subsequently, a multi-omics approach (encompassing genomic analysis, single-cell transcriptomics, and bulk transcriptomics) was employed to thoroughly elucidate the prognostic signatures.
Results: Analysis of the HCC single-cell transcriptomes revealed significant efferocytotic activity in macrophages, endothelial cells, and fibroblasts within the HCC microenvironment. We then constructed a weighted co-expression network and identified six modules, among which the brown module (168 genes) was most highly correlated with the efferocytosis score (cor = 0.84). Using the univariate Cox regression analysis, 33 prognostic ERGs were identified. Subsequently, a predictive model was constructed using 10 machine-learning algorithms, with the random survival forest model showing the highest predictive performance. The final model, ER.Sig, comprised nine genes and demonstrated robust prognostic capabilities across multiple datasets. High-risk patients exhibited greater intratumoral heterogeneity and higher TP53 mutation frequencies than did low-risk patients. Immune landscape analysis revealed that compared with high-risk patients, low-risk patients exhibited a more favorable immune environment, characterized by higher proportions of CD8+ T and B cells, tumor microenvironment score, immunophenoscore, and lower Tumor Immune Dysfunction and Exclusion scores, indicating better responses to immunotherapy. Additionally, an examination of an independent immunotherapy cohort (IMvigor210) demonstrated that low-risk patients exhibited more favorable responses to immunotherapy and improved prognoses than did their high-risk counterparts.
Conclusions: The developed ER.Sig effectively predicted the prognosis of patients with HCC and revealed significant differences in tumor biology and treatment responses between the risk groups.
{"title":"Single-cell transcriptomic analysis reveals efferocytosis signature predicting immunotherapy response in hepatocellular carcinoma.","authors":"Longhu Li, Guangyao Li, Wangfeng Zhai","doi":"10.1016/j.dld.2025.01.196","DOIUrl":"https://doi.org/10.1016/j.dld.2025.01.196","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is a substantial global health challenge owing to its high mortality rate and limited therapeutic options. We aimed to develop an efferocytosis-related gene signature (ER.Sig) and conduct a transcriptomic analysis to predict the prognosis and immunotherapeutic responses of patients with HCC.</p><p><strong>Methods: </strong>Single-cell RNA sequencing data and bulk RNA sequencing data were obtained from public databases. Based on single-sample gene set enrichment analysis and Weighted Gene Co-expression Network analyses, efferocytosis-related genes (ERGs) were selected at both the single-cell and bulk transcriptome levels. A machine-learning framework employing ten different algorithms was used to develop the ER.Sig. Subsequently, a multi-omics approach (encompassing genomic analysis, single-cell transcriptomics, and bulk transcriptomics) was employed to thoroughly elucidate the prognostic signatures.</p><p><strong>Results: </strong>Analysis of the HCC single-cell transcriptomes revealed significant efferocytotic activity in macrophages, endothelial cells, and fibroblasts within the HCC microenvironment. We then constructed a weighted co-expression network and identified six modules, among which the brown module (168 genes) was most highly correlated with the efferocytosis score (cor = 0.84). Using the univariate Cox regression analysis, 33 prognostic ERGs were identified. Subsequently, a predictive model was constructed using 10 machine-learning algorithms, with the random survival forest model showing the highest predictive performance. The final model, ER.Sig, comprised nine genes and demonstrated robust prognostic capabilities across multiple datasets. High-risk patients exhibited greater intratumoral heterogeneity and higher TP53 mutation frequencies than did low-risk patients. Immune landscape analysis revealed that compared with high-risk patients, low-risk patients exhibited a more favorable immune environment, characterized by higher proportions of CD8+ T and B cells, tumor microenvironment score, immunophenoscore, and lower Tumor Immune Dysfunction and Exclusion scores, indicating better responses to immunotherapy. Additionally, an examination of an independent immunotherapy cohort (IMvigor210) demonstrated that low-risk patients exhibited more favorable responses to immunotherapy and improved prognoses than did their high-risk counterparts.</p><p><strong>Conclusions: </strong>The developed ER.Sig effectively predicted the prognosis of patients with HCC and revealed significant differences in tumor biology and treatment responses between the risk groups.</p>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.dld.2024.09.020
Franco Curci , Chiara Rubino , Mariangela Stinco , Simona Carrera , Sandra Trapani , Elisa Bartolini , Giuseppe Indolfi
Background
Autoimmune liver disease (AILD) encompasses autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC) and primary sclerosing cholangitis (PSC). A unified disease process evolving over time through these entities has been recently suggested. From this perspective, this study aimed to compare the characteristics of childhood-onset AILD at baseline and after a medium-to-long term follow-up period.
Methods
Paediatric-onset cases of AILD diagnosed between 1992 and 2023 at a tertiary-care centre were reviewed. Patients transitioned to adult-care by the time of data collection were asked for clinical updates.
Results
Fifty-five patients were included (AIH = 20, ASC =22, PSC =13). AIH, ASC and PSC exhibited increasing age at the onset (AIH to PSC, p < 0.01). The area under the receiver operating characteristic curve for gamma-glutamyltranspeptidase (GGT) combined with alkaline phosphatase/aspartate aminotransferase (ALP/AST) ratio in predicting sclerosing cholangitis was 0.94, with a sensitivity of 86 % and a specificity of 94 %. At the last follow-up (median duration 5,8 years, interquartile range [IQR] 2,9–10,2, n = 45), 15 patients (33 %) developed portal hypertension, 2 patients (4 %) underwent liver transplantation, no patient died.
Conclusion
A cohort of childhood-onset AILD managed at a single centre reveals a temporal trend in the onset of AIH, ASC and PSC, with progressively older ages. Elevated GGT levels combined with a high ALP/AST ratio predict the diagnosis of sclerosing cholangitis. The occurrence of liver-related adverse events in one-third of patients highlights the progressive nature of paediatric-onset AILD.
{"title":"Paediatric-onset autoimmune liver disease: Insights from a monocentric experience","authors":"Franco Curci , Chiara Rubino , Mariangela Stinco , Simona Carrera , Sandra Trapani , Elisa Bartolini , Giuseppe Indolfi","doi":"10.1016/j.dld.2024.09.020","DOIUrl":"10.1016/j.dld.2024.09.020","url":null,"abstract":"<div><h3>Background</h3><div>Autoimmune liver disease (AILD) encompasses autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC) and primary sclerosing cholangitis (PSC). A unified disease process evolving over time through these entities has been recently suggested. From this perspective, this study aimed to compare the characteristics of childhood-onset AILD at baseline and after a medium-to-long term follow-up period.</div></div><div><h3>Methods</h3><div>Paediatric-onset cases of AILD diagnosed between 1992 and 2023 at a tertiary-care centre were reviewed. Patients transitioned to adult-care by the time of data collection were asked for clinical updates.</div></div><div><h3>Results</h3><div>Fifty-five patients were included (AIH = 20, ASC =22, PSC =13). AIH, ASC and PSC exhibited increasing age at the onset (AIH to PSC, <em>p</em> < 0.01). The area under the receiver operating characteristic curve for gamma-glutamyltranspeptidase (GGT) combined with alkaline phosphatase/aspartate aminotransferase (ALP/AST) ratio in predicting sclerosing cholangitis was 0.94, with a sensitivity of 86 % and a specificity of 94 %. At the last follow-up (median duration 5,8 years, interquartile range [IQR] 2,9–10,2, <em>n</em> = 45), 15 patients (33 %) developed portal hypertension, 2 patients (4 %) underwent liver transplantation, no patient died.</div></div><div><h3>Conclusion</h3><div>A cohort of childhood-onset AILD managed at a single centre reveals a temporal trend in the onset of AIH, ASC and PSC, with progressively older ages. Elevated GGT levels combined with a high ALP/AST ratio predict the diagnosis of sclerosing cholangitis. The occurrence of liver-related adverse events in one-third of patients highlights the progressive nature of paediatric-onset AILD.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 2","pages":"Pages 494-501"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.dld.2024.09.025
Alessandro Parente , Flavio Milana , Shahin Hajibandeh , Shahab Hajibandeh , Krishna V. Menon , Ki-Hun Kim , A. M. James Shapiro , Andrea Schlegel
Background & Aims
Liver transplantation for hepatocellular carcinoma (HCC) in metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly being diagnosed and predicted to rise further. We compared outcomes of transplantation for MASLD-related HCC versus other etiologies (OE).
Methods
Databases were searched to identify studies comparing outcomes after transplantation MASLD-related HCC with OE-related HCC. Study data were pooled using random-effects modelling. Survival outcomes were analyzed using hazard ratio (HR) for overall survival (OS) and odds ratio (OR) for 1-,3-, and 5-years OS and disease-free survival (DFS).
Results
Ten retrospective comparative studies were identified including a total number of 51′761 patients (MASLD-related HCC=6′793, OE-related HCC=44′968). There were no significant differences in time-to-even survival (HR:0.93, CI95 % 0.81–1.07,p = 0.29), 1-year (87.6% vs 88 %;OR:1.15; CI95 %0.73–1.79,p = 0.55), 3-year (77.2% vs 76 %;OR:1.36;CI95 %0.96–1.94,p = 0.08), or 5-year (67.7% vs 66.3 %;OR:1.08; CI95 %0.77–1.53,p = 0.65) OS rates between the groups. DFS was comparable at 1-year (87.9% vs. 87 %; OR:1.07,p = 0.62), 3-years (77.6% vs. 73.6 %;OR:1.66,p = 0.13) and 5-year (68% vs. 65.6 %;OR:1.37,p = 0.39).
Conclusion
This meta-analysis of the best available evidence (Level 2a) demonstrated that liver transplantation for MASLD-related and OE-related HCC has comparable survival outcomes. Given the global rise in MASLD-related HCC as indication for transplantation, larger studies from other continents, including Europe and Asia, are needed to confirm our findings.
背景和目的：因代谢功能障碍相关性脂肪性肝病（MASLD）导致的肝细胞癌（HCC）而进行肝移植的患者越来越多，而且预计会进一步增加。我们比较了MASLD相关HCC与其他病因（OE）移植的结果：对数据库进行检索，以确定比较 MASLD 相关 HCC 与 OE 相关 HCC 移植后疗效的研究。采用随机效应模型对研究数据进行汇总。使用总生存期（OS）的危险比（HR）和1、3、5年OS和无病生存期（DFS）的几率比（OR）分析生存结果：结果：共发现10项回顾性比较研究，包括51 761例患者（MASLD相关HCC=6 793例，OE相关HCC=44 968例）。在平均生存时间（HR:0.93, CI95 % 0.81-1.07,p = 0.29）、1年（87.6% vs 88 %;OR:1.15; CI95 %0.73-1.79,p = 0.55）、3年（77.2% vs 76%；OR:1.36；CI95 %0.96-1.94,p = 0.08）或5年（67.7% vs 66.3%；OR:1.08；CI95 %0.77-1.53,p = 0.65）OS率。1年（87.9% vs. 87%；OR:1.07,p = 0.62）、3年（77.6% vs. 73.6%；OR:1.66,p = 0.13）和5年（68% vs. 65.6%；OR:1.37,p = 0.39）的DFS相当：这项对现有最佳证据（2a 级）的荟萃分析表明，MASLD 相关 HCC 和 OE 相关 HCC 的肝移植存活率相当。鉴于作为移植适应症的MASLD相关HCC在全球呈上升趋势，因此需要在欧洲和亚洲等其他大洲进行更大规模的研究，以证实我们的发现。
{"title":"Liver transplant for hepatocellular carcinoma in metabolic dysfunction-associated steatotic liver disease versus other etiologies: A meta-analysis","authors":"Alessandro Parente , Flavio Milana , Shahin Hajibandeh , Shahab Hajibandeh , Krishna V. Menon , Ki-Hun Kim , A. M. James Shapiro , Andrea Schlegel","doi":"10.1016/j.dld.2024.09.025","DOIUrl":"10.1016/j.dld.2024.09.025","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Liver transplantation for hepatocellular carcinoma (HCC) in metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly being diagnosed and predicted to rise further. We compared outcomes of transplantation for MASLD-related HCC versus other etiologies (OE).</div></div><div><h3>Methods</h3><div>Databases were searched to identify studies comparing outcomes after transplantation MASLD-related HCC with OE-related HCC. Study data were pooled using random-effects modelling. Survival outcomes were analyzed using hazard ratio (HR) for overall survival (OS) and odds ratio (OR) for 1-,3-, and 5-years OS and disease-free survival (DFS).</div></div><div><h3>Results</h3><div>Ten retrospective comparative studies were identified including a total number of 51′761 patients (MASLD-related HCC=6′793<strong>,</strong> OE-related HCC=44′968). There were no significant differences in time-to-even survival (HR:0.93, CI<sub>95 %</sub> 0.81–1.07,<em>p</em> = 0.29), 1-year (87.6% vs 88 %;OR:1.15; CI<sub>95 %</sub>0.73–1.79,<em>p</em> = 0.55), 3-year (77.2% vs 76 %;OR:1.36;CI<sub>95 %</sub>0.96–1.94,<em>p</em> = 0.08), or 5-year (67.7% vs 66.3 %;OR:1.08; CI<sub>95 %</sub>0.77–1.53,<em>p</em> = 0.65) OS rates between the groups. DFS was comparable at 1-year (87.9% vs. 87 %; OR:1.07,<em>p</em> = 0.62), 3-years (77.6% vs. 73.6 %;OR:1.66,<em>p</em> = 0.13) and 5-year (68% vs. 65.6 %;OR:1.37,<em>p</em> = 0.39).</div></div><div><h3>Conclusion</h3><div>This meta-analysis of the best available evidence (Level 2a) demonstrated that liver transplantation for MASLD-related and OE-related HCC has comparable survival outcomes. Given the global rise in MASLD-related HCC as indication for transplantation, larger studies from other continents, including Europe and Asia, are needed to confirm our findings.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 2","pages":"Pages 362-369"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.dld.2024.11.016
Beatriz Alejandra Sánchez-Jiménez , Félix I. Téllez-Ávila
{"title":"The proliferation of systematic review and meta-analysis and the need to avoid redundancy","authors":"Beatriz Alejandra Sánchez-Jiménez , Félix I. Téllez-Ávila","doi":"10.1016/j.dld.2024.11.016","DOIUrl":"10.1016/j.dld.2024.11.016","url":null,"abstract":"","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 2","pages":"Page 658"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.dld.2025.01.057
M. Trucchi , L.G. Di Pasqua , F. Protopapa , S. Lotti , A.C. Croce , M. Vairetti , F. Nicoletti , A. Ferrigno
Introduction and Aim
Recent studies highlight the role of metabotropic glutamate receptor type 5 (mGluR5) in hepatic steatosis, where its hyperactivation in hepatic stellate cells (HSCs) drives fat accumulation in hepatocytes (Choi et al., 2019). Previous research demonstrated that 2-methyl-6-(phenylethynyl)pyridine (MPEP), a negative allosteric modulator of mGluR5, reduces lipid deposition in HepG2 cells exposed to an oleate/palmitate-induced steatosis model (Ferrigno et al., 2020). This study aimed to evaluate mGluR5’s role in lipid metabolism using negative allosteric modulators (MPEP, Fenobam), an orthosteric antagonist (carboxyphenylglycine, CPG), and an orthosteric agonist ((S)-3,5-dihydroxyphenylglycine, DHPG). Additionally, we explored whether MPEP's effects involve activation of AMP-activated protein kinase (AMPK), a critical regulator of lipid metabolism linked to ATP depletion (Ferrigno et al., 2018).
Materials and Methods
Lipid accumulation was induced in HepG2 cells using 2 mM oleate/palmitate (O/P) for 24 hours. Cells were treated with MPEP (0.3-3-30 μM), Fenobam (1-25-50 μM), and CPG (100-150-200 μM), alone or with the AMPK inhibitor (Compound C 0.1-1-10 μM). Non-steatotic cells received DHPG (100-200-300 μM) alone or with 30 μM MPEP. Lipid content was visualized with Nile Red dye and quantified via ImageJ; cell viability was assessed via MTT assay. ATP levels were measured using a luciferin-luciferase assay, and the p-AMPK/AMPK ratio was analyzed by Western blot.
Results
In steatotic HepG2 cells, MPEP, Fenobam, and CPG significantly reduced lipid accumulation dose-dependently. DHPG increased lipid content in non-steatotic cells, but co-treatment with MPEP reversed this effect. MPEP, uniquely among the compounds, depleted ATP levels and activated AMPK. Compound C abolished MPEP's lipid-lowering effects, confirming AMPK's role. Western blot showed increased p-AMPK/AMPK ratios in MPEP-treated steatotic cells.
Conclusion
mGluR5 inhibition reduces lipid accumulation in an in vitro steatosis model. MPEP engages an AMPK-mediated pathway, providing a dual mechanism against hepatic steatosis and highlighting its therapeutic potential.
{"title":"MPEP combines mGluR5 inhibition and AMPK activation to reduce hepatic steatosis","authors":"M. Trucchi , L.G. Di Pasqua , F. Protopapa , S. Lotti , A.C. Croce , M. Vairetti , F. Nicoletti , A. Ferrigno","doi":"10.1016/j.dld.2025.01.057","DOIUrl":"10.1016/j.dld.2025.01.057","url":null,"abstract":"<div><h3>Introduction and Aim</h3><div>Recent studies highlight the role of metabotropic glutamate receptor type 5 (mGluR5) in hepatic steatosis, where its hyperactivation in hepatic stellate cells (HSCs) drives fat accumulation in hepatocytes (Choi et al., 2019). Previous research demonstrated that 2-methyl-6-(phenylethynyl)pyridine (MPEP), a negative allosteric modulator of mGluR5, reduces lipid deposition in HepG2 cells exposed to an oleate/palmitate-induced steatosis model (Ferrigno et al., 2020). This study aimed to evaluate mGluR5’s role in lipid metabolism using negative allosteric modulators (MPEP, Fenobam), an orthosteric antagonist (carboxyphenylglycine, CPG), and an orthosteric agonist ((S)-3,5-dihydroxyphenylglycine, DHPG). Additionally, we explored whether MPEP's effects involve activation of AMP-activated protein kinase (AMPK), a critical regulator of lipid metabolism linked to ATP depletion (Ferrigno et al., 2018).</div></div><div><h3>Materials and Methods</h3><div>Lipid accumulation was induced in HepG2 cells using 2 mM oleate/palmitate (O/P) for 24 hours. Cells were treated with MPEP (0.3-3-30 μM), Fenobam (1-25-50 μM), and CPG (100-150-200 μM), alone or with the AMPK inhibitor (Compound C 0.1-1-10 μM). Non-steatotic cells received DHPG (100-200-300 μM) alone or with 30 μM MPEP. Lipid content was visualized with Nile Red dye and quantified via ImageJ; cell viability was assessed via MTT assay. ATP levels were measured using a luciferin-luciferase assay, and the p-AMPK/AMPK ratio was analyzed by Western blot.</div></div><div><h3>Results</h3><div>In steatotic HepG2 cells, MPEP, Fenobam, and CPG significantly reduced lipid accumulation dose-dependently. DHPG increased lipid content in non-steatotic cells, but co-treatment with MPEP reversed this effect. MPEP, uniquely among the compounds, depleted ATP levels and activated AMPK. Compound C abolished MPEP's lipid-lowering effects, confirming AMPK's role. Western blot showed increased p-AMPK/AMPK ratios in MPEP-treated steatotic cells.</div></div><div><h3>Conclusion</h3><div>mGluR5 inhibition reduces lipid accumulation in an in vitro steatosis model. MPEP engages an AMPK-mediated pathway, providing a dual mechanism against hepatic steatosis and highlighting its therapeutic potential.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 ","pages":"Page S30"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.dld.2025.01.058
C. Simoni , J. Testa , L. Maroni , B. Castiglioni
Background
Enterobius vermicularis is a common worm infestation of the bowel lumen; it has rarely been found outside the gastrointestinal tract. We review a case of hepatic enterobiasis mimicking haematologic disease.
Case description
In November 2021 and 2022 a 55 yo man developed two episodes of urticaria treated with steroids. During the first episode groin itching was also reported.
Blood tests showed eosinophilia (WBC 19030/mm3, Eos 67.1%), augmented total IgE (2108 IU/mL) and LFTs (liver function tests) (AST 69 IU/L, ALT 91 IU/L, GGT 127 IU/L) with negative viral hepatitis serologies as well as autoimmunity (ANA, antiDNA AMA, ASMA, antiLKM, ENA, ANCA). No ova nor worms were found in faeces (single sample tested). Sinus and chest CT scan showed no signs of Churg Strauss syndrome.
Liver ultrasound (LUS) showed mild hepatomegaly, non-homogeneous echo pattern with centimetric hypoechoic areas (Dec/2022). Abdomen MRI showed multiple and diffuse subverted structures of the liver (suggestive of lymphoma) and multiple lymph nodes (Apr/2023).
Due to persisting eosinophilia (WBC 8400/mm3, Eos 33.4%) and augmented total IgE (752 IU/mL) with abnormal LFTs (AST 59 IU/L, ALT 51 IU/L, GGT 138 IU/L, ALP 226 IU/L), patient underwent a first liver biopsy, suggestive of infectious etiopathogenesis: massive and confluent necrosis surrounded by histiocytes and numerous eosinophils, mild cholestasis and some eosinophils within the lobules, lymphohistiocytic inflammation with some eosinophils in the pericentral location; PAS, GMS, GROCOTT, WS and ZN stains were negative.
In May 2023 faeces were tested again: 1 out of 3 samples revealed Enterobius vermicularis ova. Serologies for Schistosoma and Trichinella were negative, as well as endoscopic searching for Anisakis.
Albendazole treatment (400mg once/weekly for 8 weeks) was administered, resulting in normalization of eosinophils count (4.8%, 300/mm3) and LFTs (AST 24 IU/L, ALT 27 IU/L, GGT 64 IU/L); moreover, a second liver biopsy showing normal pattern was performed after the aforementioned therapy, 6 months after the first one. Finally, a liver MRI confirmed the complete resolution of the abnormalities previously reported.
Conclusions
Ectopic localization of Enterobius vermicularis is rare. International literature reports six cases of liver infection, only two with modern imaging available, describing liver lesions as ill-defined, while diffuse hypoechoic areas were observed in our imaging. Treatment with albendazole (chronic recurrent course) resulted in normalization of the eosinophil count and LFTs; furthermore, histopathological lesions (necrosis and eosinophils infiltration) were no longer observed on the liver biopsy after appropriate therapy.
{"title":"Enterobius vermicularis infection mimicking liver malignancy","authors":"C. Simoni , J. Testa , L. Maroni , B. Castiglioni","doi":"10.1016/j.dld.2025.01.058","DOIUrl":"10.1016/j.dld.2025.01.058","url":null,"abstract":"<div><h3>Background</h3><div><em>Enterobius vermicularis</em> is a common worm infestation of the bowel lumen; it has rarely been found outside the gastrointestinal tract. We review a case of hepatic enterobiasis mimicking haematologic disease.</div></div><div><h3>Case description</h3><div>In November 2021 and 2022 a 55 yo man developed two episodes of urticaria treated with steroids. During the first episode groin itching was also reported.</div><div>Blood tests showed eosinophilia (WBC 19030/mm3, Eos 67.1%), augmented total IgE (2108 IU/mL) and LFTs (liver function tests) (AST 69 IU/L, ALT 91 IU/L, GGT 127 IU/L) with negative viral hepatitis serologies as well as autoimmunity (ANA, antiDNA AMA, ASMA, antiLKM, ENA, ANCA). No ova nor worms were found in faeces (single sample tested). Sinus and chest CT scan showed no signs of Churg Strauss syndrome.</div><div>Liver ultrasound (LUS) showed mild hepatomegaly, non-homogeneous echo pattern with centimetric hypoechoic areas (Dec/2022). Abdomen MRI showed multiple and diffuse subverted structures of the liver (suggestive of lymphoma) and multiple lymph nodes (Apr/2023).</div><div>Due to persisting eosinophilia (WBC 8400/mm3, Eos 33.4%) and augmented total IgE (752 IU/mL) with abnormal LFTs (AST 59 IU/L, ALT 51 IU/L, GGT 138 IU/L, ALP 226 IU/L), patient underwent a first liver biopsy, suggestive of infectious etiopathogenesis: massive and confluent necrosis surrounded by histiocytes and numerous eosinophils, mild cholestasis and some eosinophils within the lobules, lymphohistiocytic inflammation with some eosinophils in the pericentral location; PAS, GMS, GROCOTT, WS and ZN stains were negative.</div><div>In May 2023 faeces were tested again: 1 out of 3 samples revealed <em>Enterobius vermicularis</em> ova. Serologies for <em>Schistosoma</em> and <em>Trichinella</em> were negative, as well as endoscopic searching for <em>Anisakis</em>.</div><div>Albendazole treatment (400mg once/weekly for 8 weeks) was administered, resulting in normalization of eosinophils count (4.8%, 300/mm3) and LFTs (AST 24 IU/L, ALT 27 IU/L, GGT 64 IU/L); moreover, a second liver biopsy showing normal pattern was performed after the aforementioned therapy, 6 months after the first one. Finally, a liver MRI confirmed the complete resolution of the abnormalities previously reported.</div></div><div><h3>Conclusions</h3><div>Ectopic localization of <em>Enterobius vermicularis</em> is rare. International literature reports six cases of liver infection, only two with modern imaging available, describing liver lesions as ill-defined, while diffuse hypoechoic areas were observed in our imaging. Treatment with albendazole (chronic recurrent course) resulted in normalization of the eosinophil count and LFTs; furthermore, histopathological lesions (necrosis and eosinophils infiltration) were no longer observed on the liver biopsy after appropriate therapy.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 ","pages":"Pages S30-S31"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.dld.2025.01.088
M. Giuffre , S. Kresevic , M. Ajcevic , L. Crocè , D. Shung
Background
Large Language Models (LLMs) may be useful for clinical tasks that require reasoning over different information sources. LLMs could be regarded as intelligent "agents" with internal planning abilities, enabling them to engage in multi-step reasoning and interact with other agents or external users. Hepatitis C Virus (HCV) management is a potential area where LLM-enabled agents could be useful, since treatment decisions require consideration of genotype, treatment history, liver fibrosis extent, and drug-drug interactions.
Aim
To evaluate the performance of different LLM agent-based configurations in automating HCV treatment decisions and to determine whether specialized multi-agent architectures improve prescription accuracy compared to single-agent approaches.
Material and Methods
We developed 50 clinical cases focusing on therapeutic regimen prescription. Cases included genotype, prior treatment history, fibrosis status, and concurrent medications. We compared multiple configurations using OpenAI's GPT-3.5 and GPT-4o, fine-tuned with HCV treatment guidelines. Different agent architectures were tested: single agent (one LLM extracting all data), multi-agent (three specialized LLMs for data extraction plus prescriber), and specialized multi-agent (four specialized extraction agents plus prescriber). Each agent accessed specific guideline sections relevant to its task. Performance was compared to baseline fine-tuned models.
Results
Using GPT-3.5, the baseline model achieved 24% prescription accuracy. The single agent configuration reached 50% (p=0.007), multi-agent 76% (p<0.001), and specialized multi-agent 89% (p<0.001). With GPT-4, performance improved significantly: baseline 35% accuracy, single agent 65% (p=0.005), multi-agent 88% (p<0.001), and specialized multi-agent 94% (p<0.001).
Conclusions
Specialized multi-agent LLM frameworks significantly improve HCV treatment recommendation accuracy, with GPT-4 showing superior performance. The agent-based approach demonstrates the potential for complex clinical decision-making. Future work should validate these findings in real-world settings and explore integration with clinical decision-support systems.
{"title":"Large Language Model Agent-Based Framework for automated Treatment Prescription in Patients with Chronic Hepatitis C Virus Infection","authors":"M. Giuffre , S. Kresevic , M. Ajcevic , L. Crocè , D. Shung","doi":"10.1016/j.dld.2025.01.088","DOIUrl":"10.1016/j.dld.2025.01.088","url":null,"abstract":"<div><h3>Background</h3><div>Large Language Models (LLMs) may be useful for clinical tasks that require reasoning over different information sources. LLMs could be regarded as intelligent \"agents\" with internal planning abilities, enabling them to engage in multi-step reasoning and interact with other agents or external users. Hepatitis C Virus (HCV) management is a potential area where LLM-enabled agents could be useful, since treatment decisions require consideration of genotype, treatment history, liver fibrosis extent, and drug-drug interactions.</div></div><div><h3>Aim</h3><div>To evaluate the performance of different LLM agent-based configurations in automating HCV treatment decisions and to determine whether specialized multi-agent architectures improve prescription accuracy compared to single-agent approaches.</div></div><div><h3>Material and Methods</h3><div>We developed 50 clinical cases focusing on therapeutic regimen prescription. Cases included genotype, prior treatment history, fibrosis status, and concurrent medications. We compared multiple configurations using OpenAI's GPT-3.5 and GPT-4o, fine-tuned with HCV treatment guidelines. Different agent architectures were tested: single agent (one LLM extracting all data), multi-agent (three specialized LLMs for data extraction plus prescriber), and specialized multi-agent (four specialized extraction agents plus prescriber). Each agent accessed specific guideline sections relevant to its task. Performance was compared to baseline fine-tuned models.</div></div><div><h3>Results</h3><div>Using GPT-3.5, the baseline model achieved 24% prescription accuracy. The single agent configuration reached 50% (p=0.007), multi-agent 76% (p<0.001), and specialized multi-agent 89% (p<0.001). With GPT-4, performance improved significantly: baseline 35% accuracy, single agent 65% (p=0.005), multi-agent 88% (p<0.001), and specialized multi-agent 94% (p<0.001).</div></div><div><h3>Conclusions</h3><div>Specialized multi-agent LLM frameworks significantly improve HCV treatment recommendation accuracy, with GPT-4 showing superior performance. The agent-based approach demonstrates the potential for complex clinical decision-making. Future work should validate these findings in real-world settings and explore integration with clinical decision-support systems.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 ","pages":"Pages S46-S47"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.dld.2025.01.017
G. Amaddeo , M. Allaire , M.S. Franzè , C. Dupré , S. Caruso , T. Antonini , Y. Chouik , H. Regnault , A. Beaufrère , J. Ursic-Bedoya , M. Ningarhari , T. Uguen , A. Jaillais , O. Roux , L. Blaise , R. Gerolami , A. Pascale , R. Brustia , D. Sommacale , J. Dumortier , V. Leroy
Introduction
Immunotherapy is an attractive strategy for downstaging/bridging hepatocellular carcinoma (HCC) to liver transplantation (LT).
Aims
This multicenter study reports the results of HCC-transplanted patients in ten French liver transplant centers in this context.
Patients and Methods
Clinical, biological, and radiological data were collected for each patient at the beginning and end of immunotherapy and before LT. The primary endpoint was the tolerance and effectiveness of LT.
Results
Twenty-one patients [majority of men (17/21); median age 62 years (57-64), BCLC B stage in 14/21 patients (66.7%)] who underwent LT for HCC after immunotherapy were included. HCC was multi-nodular in 17/21 (81%) cases, with a median size of the largest nodule of 36 mm (21-60). Thirteen patients had an AFP score >2 (downstaging group) and 8 of ≤2 (bridging group). Patients in the downstaging group were beyond Milan criteria, and 3 in the bridging group (p=0.006). Sixteen patients (76.2%) received Atezolizumab/Bevacizumab during 8.5 cycles (4.7-14). At the end of immunotherapy, most patients shifted to an early/intermediate BCLC stage (p=0.001) and reached Milan criteria (57.1%, p=0.023). The AFP score remained >2 in 2 cases (9.5%) (p=0.003). The median interval between the last immunotherapy cycle and LT was 5.1 (2.7-9.3) months. All patients except 3 received standard immunosuppressive treatment. Two cases (10%) of rejection occurred, resolved after increasing immunosuppression. Early serious adverse events occurred in 6 patients (28.5%), 5 being fatal (27%). Two patients (10.5%) had an HCC recurrence post-LT. On explant pathology, no residual tumor was detected in 6 cases (28.6%) and partial necrosis in 7 (41.2%). The R3-AFP score stratified patients into 3 at very low (14.3%), 8 at low (38.1%), and 10 at high (47.6%) recurrence risk.
Conclusion
LT following immunotherapy is feasible in selected patients with HCC and has an acceptable risk of rejection. However, the high immediate mortality observed requires further exploration in prospective studies.
{"title":"Feasibility and effectiveness of liver transplantation following immunotherapy in patients with hepatocellular carcinoma","authors":"G. Amaddeo , M. Allaire , M.S. Franzè , C. Dupré , S. Caruso , T. Antonini , Y. Chouik , H. Regnault , A. Beaufrère , J. Ursic-Bedoya , M. Ningarhari , T. Uguen , A. Jaillais , O. Roux , L. Blaise , R. Gerolami , A. Pascale , R. Brustia , D. Sommacale , J. Dumortier , V. Leroy","doi":"10.1016/j.dld.2025.01.017","DOIUrl":"10.1016/j.dld.2025.01.017","url":null,"abstract":"<div><h3>Introduction</h3><div>Immunotherapy is an attractive strategy for downstaging/bridging hepatocellular carcinoma (HCC) to liver transplantation (LT).</div></div><div><h3>Aims</h3><div>This multicenter study reports the results of HCC-transplanted patients in ten French liver transplant centers in this context.</div></div><div><h3>Patients and Methods</h3><div>Clinical, biological, and radiological data were collected for each patient at the beginning and end of immunotherapy and before LT. The primary endpoint was the tolerance and effectiveness of LT.</div></div><div><h3>Results</h3><div>Twenty-one patients [majority of men (17/21); median age 62 years (57-64), BCLC B stage in 14/21 patients (66.7%)] who underwent LT for HCC after immunotherapy were included. HCC was multi-nodular in 17/21 (81%) cases, with a median size of the largest nodule of 36 mm (21-60). Thirteen patients had an AFP score >2 (downstaging group) and 8 of ≤2 (bridging group). Patients in the downstaging group were beyond Milan criteria, and 3 in the bridging group (p=0.006). Sixteen patients (76.2%) received Atezolizumab/Bevacizumab during 8.5 cycles (4.7-14). At the end of immunotherapy, most patients shifted to an early/intermediate BCLC stage (p=0.001) and reached Milan criteria (57.1%, p=0.023). The AFP score remained >2 in 2 cases (9.5%) (p=0.003). The median interval between the last immunotherapy cycle and LT was 5.1 (2.7-9.3) months. All patients except 3 received standard immunosuppressive treatment. Two cases (10%) of rejection occurred, resolved after increasing immunosuppression. Early serious adverse events occurred in 6 patients (28.5%), 5 being fatal (27%). Two patients (10.5%) had an HCC recurrence post-LT. On explant pathology, no residual tumor was detected in 6 cases (28.6%) and partial necrosis in 7 (41.2%). The R3-AFP score stratified patients into 3 at very low (14.3%), 8 at low (38.1%), and 10 at high (47.6%) recurrence risk.</div></div><div><h3>Conclusion</h3><div>LT following immunotherapy is feasible in selected patients with HCC and has an acceptable risk of rejection. However, the high immediate mortality observed requires further exploration in prospective studies.</div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 ","pages":"Page S10"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.dld.2025.01.011
E. Dileo , C. Rosso , M. Parasiliti-Caprino , G.P. Caviglia , F. Ponzetto , L. Leoni , G. Pennisi , A. Armandi , M. Guariglia , F. Saba , M. Maccario , S. Petta , G. Mengozzi , E. Bugianesi
Introduction
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a sexually dimorphic condition, characterized by a high prevalence in men compared to premenopausal women, but the reverse is true after menopause. Steroids, including glucocorticoids and sex hormones, regulate both glucose and lipid metabolism, and their perturbation may exert a detrimental effect on metabolic pathways promoting liver damage.
Aim
The aim of this study was to shed light on sexual dimorphism in patients with MASLD through a targeted steroidomic approach.
Materials and Methods
We enrolled 463 consecutive patients (males n=275 [59%]; females n=188 [41%]) with biopsy-proven MASLD and 112 healthy controls (HC) (males n=55 [49%]; females n=57 [51%]). A panel of 26 steroids (including glucocorticoids, androgens and their representative glucuro- and sulpho-conjugated metabolites) was measured by liquid chromatography coupled to tandem mass spectrometry. For statistical analysis, we stratified the whole cohort according to sex and age, using 50 years(y) as a cut-off. Advanced fibrosis was defined as F≥3.
Results
By comparing MASLD subjects and HC, we observed an increase in glucocorticoid levels in MASLD men<50y, and an increase in testosterone levels in MASLD women ≥50y compared to the corresponding HC groups. Concerning MASLD group, the prevalence of F≥3 was 36% (men/women 31%/45%, p=0.061). Similarly, we observed an increase in glucocorticoids levels in both MASLD men and women <50y with F≥3 compared to those without advanced hepatic fibrosis. In addition, in MASLD women with F≥3, regardless of age, we observed an increase in androgens metabolites, but a decrease in sulphate compounds.
Conclusions
In patients with MASLD, we identified different steroids profiles according to gender and age that varied according to the severity of hepatic fibrosis. Further studies are needed to understand the molecular basis of sexual dimorphism in the context of MASLD.
Funded by HORIZON-HLTH-2023-ENVHLTH-02 program for the consortium EDC-MASLD, g.a. n. 101136259.
{"title":"Impact of sexual dimorphism on liver damage in patients with metabolic-dysfunction associated steatotic liver disease","authors":"E. Dileo , C. Rosso , M. Parasiliti-Caprino , G.P. Caviglia , F. Ponzetto , L. Leoni , G. Pennisi , A. Armandi , M. Guariglia , F. Saba , M. Maccario , S. Petta , G. Mengozzi , E. Bugianesi","doi":"10.1016/j.dld.2025.01.011","DOIUrl":"10.1016/j.dld.2025.01.011","url":null,"abstract":"<div><h3>Introduction</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a sexually dimorphic condition, characterized by a high prevalence in men compared to premenopausal women, but the reverse is true after menopause. Steroids, including glucocorticoids and sex hormones, regulate both glucose and lipid metabolism, and their perturbation may exert a detrimental effect on metabolic pathways promoting liver damage.</div></div><div><h3>Aim</h3><div>The aim of this study was to shed light on sexual dimorphism in patients with MASLD through a targeted steroidomic approach.</div></div><div><h3>Materials and Methods</h3><div>We enrolled 463 consecutive patients (males n=275 [59%]; females n=188 [41%]) with biopsy-proven MASLD and 112 healthy controls (HC) (males n=55 [49%]; females n=57 [51%]). A panel of 26 steroids (including glucocorticoids, androgens and their representative glucuro- and sulpho-conjugated metabolites) was measured by liquid chromatography coupled to tandem mass spectrometry. For statistical analysis, we stratified the whole cohort according to sex and age, using 50 years(y) as a cut-off. Advanced fibrosis was defined as F≥3.</div></div><div><h3>Results</h3><div>By comparing MASLD subjects and HC, we observed an increase in glucocorticoid levels in MASLD men<50y, and an increase in testosterone levels in MASLD women ≥50y compared to the corresponding HC groups. Concerning MASLD group, the prevalence of F≥3 was 36% (men/women 31%/45%, p=0.061). Similarly, we observed an increase in glucocorticoids levels in both MASLD men and women <50y with F≥3 compared to those without advanced hepatic fibrosis. In addition, in MASLD women with F≥3, regardless of age, we observed an increase in androgens metabolites, but a decrease in sulphate compounds.</div></div><div><h3>Conclusions</h3><div>In patients with MASLD, we identified different steroids profiles according to gender and age that varied according to the severity of hepatic fibrosis. Further studies are needed to understand the molecular basis of sexual dimorphism in the context of MASLD.</div><div><em>Funded by HORIZON-HLTH-2023-ENVHLTH-02 program for the consortium EDC-MASLD, g.a. n. 101136259.</em></div></div>","PeriodicalId":11268,"journal":{"name":"Digestive and Liver Disease","volume":"57 ","pages":"Pages S5-S6"},"PeriodicalIF":4.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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